The overall aim of this research is to determine the effects of marijuana (MJ) on brain connectivity in adolescents, and to establish whether such influences on complex neural networks are more pronounced in biological relatives of schizophrenia (SZ) patients. This proposal is significant because it will provide new information about the potential hazards adolescent MJ exposure poses to public health. Adolescent MJ use is a known environmental risk factor for SZ. MJ is also the most commonly used illicit drug among adolescents in the U.S. where first MJ exposure often occurs in mid-adolescence. Recent youth surveys report rising MJ usage, persistent easy MJ access, and declining perception that MJ is harmful. Activation of cannabinoid receptors is vital in regulating neural cell survival, brain development and neuroplasticity. Animal studies provide clear evidence that tetrahydrocannabinol present in MJ is deleterious to the brain, especially during the sensitive period of adolescent brain maturation. However, human neuroimaging studies have been contradictory partly due to the absence of longitudinal data on human adolescents. To address these gaps in knowledge, we will conduct a prospective MRI study of healthy adolescent volunteers without family history of SZ (HNV), and a matched sample of first-degree relatives of SZ patients. At study entry, subjects have no prior MJ use. Targeted recruitment strategies and close attention to promote subject retention will be utilized. Brain anatomic, diffusion-weighted magnetization transfer ratio, and resting-state functional MRI data are obtained at intake and 3 years later. Using reliable and well-validated assessment protocols at 6-monthly intervals, subjects will be monitored for onset and severity of emergent MJ use (expected to be 25% of intake sample). This prospective study design will yield 4 informative comparison groups (stratified by MJ use and SZ family history) providing an explicit test to reveal the unique effect of adolescent MJ exposure and of familial SZ risk on longitudinal brain changes. Specific Aims 1 and 2 utilize state-of-the-art statistical analyses to assess the impact of emergent MJ use on within-subject changes in brain structural integrity, and on differential effects in SZ relatives. he hypothesis is that adolescents with emergent MJ use will show deficits in structural brain integrity. Against a background of genetic vulnerability for SZ, biological relatives will be more susceptible to MJ's deleterious effects. Specific Aim 3 uses novel graph theory methods to quantify the topographical properties of brain structural and functional connectivity. The influence of adolescent MJ use on changes in brain network organization will be contrasted between HNV and SZ relatives. Specific Aim 4 explores secondary outcomes of neurocognition, personality traits and prodromal symptoms to develop integrative models to explain the adolescent MJ-SZ link. Thus, this proposal with its longitudinal study design and innovative network connectivity measures will advance knowledge regarding the impact adolescent MJ exposure has on public health and on SZ susceptibility.